High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis
2008; Elsevier BV; Volume: 36; Issue: 8 Linguagem: Inglês
10.1016/j.exphem.2008.03.001
ISSN1873-2399
AutoresYury L. Shevchenko, Andrei A. Novik, Kuznetsov An, B. V. Аfanasiev, Igor Lisukov, Kozlov Va, Oleg A. Rykavicin, Tatyana Ionova, В Я Мельниченко, Denis A. Fedorenko, Alexander Kulagin, Sergei V. Shamanski, Roman Ivanov, Gary J Gorodokin,
Tópico(s)Peripheral Neuropathies and Disorders
ResumoHigh-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is a new and promising approach to the treatment of multiple sclerosis (MS) patients because currently there are no effective treatment methods for this disease. In this article, we present results of a prospective clinical study of efficacy of HDIT + auto-HSCT in MS patients. The following treatment strategies were employed in the study: "early," "conventional," and "salvage/late" transplantation. Fifty patients with various types of MS were included in this study. No toxic deaths were reported among 50 MS patients; transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients. Twenty-eight patients achieved an objective improvement of neurological symptoms, defined as at least 0.5-point decrease in the Expanded Disability Status Scale (EDSS) score as compared to the baseline and confirmed during 6 months, and 17 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed during 6 months). The progression-free survival at 6 years after HDIT + auto-HSCT was 72%. Magnetic resonance imaging data were available in 37 patients before transplantation showing disease activity in 43.3%. No active, new, or enlarging lesions were registered in patients without disease progression. In conclusion, HDIT + auto-HSCT suggests positive results in management of patients with different types of MS. Identification of treatment strategies based on the level of disability, namely "early," "conventional," and "salvage/late" transplantation, appears to be feasible to improve treatment outcomes. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is a new and promising approach to the treatment of multiple sclerosis (MS) patients because currently there are no effective treatment methods for this disease. In this article, we present results of a prospective clinical study of efficacy of HDIT + auto-HSCT in MS patients. The following treatment strategies were employed in the study: "early," "conventional," and "salvage/late" transplantation. Fifty patients with various types of MS were included in this study. No toxic deaths were reported among 50 MS patients; transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients. Twenty-eight patients achieved an objective improvement of neurological symptoms, defined as at least 0.5-point decrease in the Expanded Disability Status Scale (EDSS) score as compared to the baseline and confirmed during 6 months, and 17 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed during 6 months). The progression-free survival at 6 years after HDIT + auto-HSCT was 72%. Magnetic resonance imaging data were available in 37 patients before transplantation showing disease activity in 43.3%. No active, new, or enlarging lesions were registered in patients without disease progression. In conclusion, HDIT + auto-HSCT suggests positive results in management of patients with different types of MS. Identification of treatment strategies based on the level of disability, namely "early," "conventional," and "salvage/late" transplantation, appears to be feasible to improve treatment outcomes. Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) caused by autoimmune reactivity of T cells toward CNS myelin components. There is increased evidence that the disease is associated with aberrant immune responses [1Martin R. McFarland H.F. McFarlin D.E. Immunological aspects of demyelinating diseases.Annu Rev Immunol. 1992; 10: 153-187Crossref PubMed Scopus (945) Google Scholar, 2Noseworthy J.H. Lucchinetti C. Rodriguez M. Weinshenker B.G. Multiple sclerosis.N Engl J Med. 2000; 343: 938-952Crossref PubMed Scopus (2955) Google Scholar, 3Muraro P.A. McFarland H.F. Martin R. Immunological aspects of multiple sclerosis with emphasis on the potential use of autologous haemopoietic stem cell transplantation.in: Burt R.K. Marmont A.M. Stem cell therapy for autoimmune disease. Landes Bioscience, Georgetown, TX2004: 277-283Google Scholar]. MS progression inevitably leads to loss of motor function, sensitive disturbances, and cognitive impairment because of the immune-mediated demyelination and axon degeneration. MS is one of the most common neurological disorders that affects young adults mainly, and causes a gradual decrease of their quality of life. The clinical course of the disease is very heterogeneous. However, it typically presents with a relapsing-remitting course (RRMS; 80% of patients), which is followed after 5 to 15 years in about 70% of patients by a so-called secondary progressive phase (SPMS) [2Noseworthy J.H. Lucchinetti C. Rodriguez M. Weinshenker B.G. Multiple sclerosis.N Engl J Med. 2000; 343: 938-952Crossref PubMed Scopus (2955) Google Scholar]. Ten to fifteen percent of patients have a primary progressive course, which is characterized by a steady progression from onset with or without any acute exacerbations (progressive relapsing MS [PRMS] and primary progressive MS [PPMS], respectively). One of the reasons why conventional therapies do not provide satisfactory control of MS is their inability to eradicate self-specific T-cell clones. Recently, high-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) was proposed as a new and promising therapy for MS patients [4Fassas A. Anagnostopoulos A. Kazis A. et al.Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study.Bone Marrow Transplant. 1997; 20: 631-638Crossref PubMed Scopus (243) Google Scholar, 5Burt R.K. Traynor A.E. Cohen B. et al.T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients.Bone Marrow Transplant. 1998; 21: 537-541Crossref PubMed Scopus (91) Google Scholar]. The rationale is that ablation of aberrant immune system followed by reconstitution of the new immune system from hematopoietic stem cells can alter the characteristics of the T-cell responses and other immunological properties, which may improve the clinical course of MS. Since 1995, several clinical studies have addressed the issue of feasibility and efficacy of HDIT + auto-HSCT in MS and a certain clinical benefit was shown [6Fassas A. Anagnostopoulos A. Kazis A. et al.Autologous stem cell transplantation in progressive multiple sclerosis—an interim analysis of efficacy.J Clin Immunol. 2000; 20: 24-30Crossref PubMed Scopus (165) Google Scholar, 7Fassas A. Passweg J.R. Anagnostopoulos A. et al.Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study.J Neurol. 2002; 249: 1088-1097Crossref PubMed Scopus (229) Google Scholar, 8Kozak T. Havrdova E. Pit'ha J. et al.High-dose immunosuppressive therapy with PBPC support in the treatment of poor risk multiple sclerosis.Bone Marrow Transplant. 2000; 25: 525-531Crossref PubMed Scopus (104) Google Scholar, 9Openshaw H. Lund B. Kashyap A. et al.Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning report of toxicity and immunological monitoring.Biol Blood Marrow Transplant. 2000; 25: 525-575Google Scholar, 10Burt R.K. Cohen B.A. Russell E. et al.Hematopoietic stem cell transplantation for progressive multiple sclerosis; failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores.Blood. 2003; 102: 2373-2378Crossref PubMed Scopus (172) Google Scholar, 11Fassas A. Nash R. Multiple sclerosis.Best Pract Res Clin Hematol. 2004; 17: 247-262Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 12Nash R.A. Bowen J.D. McSweeney P.A. et al.High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis.Blood. 2003; 102: 2364-2372Crossref PubMed Scopus (198) Google Scholar, 13Saccardi R. Mancardi G.L. Solari A. et al.Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life.Blood. 2005; 105: 2601-2607Crossref PubMed Scopus (144) Google Scholar, 14Burt R.K. Cohen B. Rose J. et al.Haematopoietic stem cell transplantation for multiple sclerosis.Arch Neurol. 2005; 62: 860-864Crossref PubMed Scopus (59) Google Scholar]. The BCNU, etoposide, cytarabine, and melphalan (BEAM) conditioning regimen is considered to be the most effective, although it is accompanied with the risk of transplant-related mortality [7Fassas A. Passweg J.R. Anagnostopoulos A. et al.Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study.J Neurol. 2002; 249: 1088-1097Crossref PubMed Scopus (229) Google Scholar, 11Fassas A. Nash R. Multiple sclerosis.Best Pract Res Clin Hematol. 2004; 17: 247-262Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. The majority of patients included in the above-mentioned studies had SPMS and were severely disabled, with an average Expanded Disability Status Scale (EDSS) score of 6.5. At the same time, the mechanism of immune recovery following auto-HSCT is poorly understood. In the study performed in four MS patients with severe disability (mean EDSS score 6.25; mean disease duration 11.5 years) two distinctive phases of T-cell−mediated immune recovery after transplantation were found and complete restoration of immune system as well as preservation of clinical effect over time were argued [15Sun W. Popat U. Hutton G. et al.Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis.Brain. 2004; 127: 996-1008Crossref PubMed Scopus (82) Google Scholar]. Therefore, information about long-term outcomes of HDIT + auto-HSCT is of much importance. At the same time, taking into account the information about high risk of transplant-related mortality and severe side effects of myeloablative conditioning regimens, the rationale to use nonmyeloablative regimens sounds reasonable [16Burt R.K. Marmont A. Oyama Yu et al.Randomized controlled trials of autologous haematopoietic stem cell transplantation for autoimmune diseases.Arthritis Rheum. 2006; 54: 3750-3760Crossref PubMed Scopus (103) Google Scholar]. In this connection we initiated a prospective Phase II multicenter trial consisting of two arms. Patients in the first arm were enrolled from 1999 to 2006 and for them BEAM conditioning was used. The second arm was opened in 2006 and for the patients in this arm, nonmyeloablative reduced BEAM regimen was chosen. By now 23 patients (median EDSS: 3.5) have been enrolled and we are expecting the analysis of this arm by 2009. Another important consideration that influenced our study design is heterogeneity of the population of MS patients. In addition, patient-selection criteria for HDIT + auto-HSCT are still unclear and the proper selection of patients for transplantation remains the key issue. We proposed three strategies of HDIT + auto-HSCT [17Shevchenko Y.L. Novik A.A. Ionova T.I. et al.Three strategies of high dose chemotherapy + autologous stem cell transplantation in autoimmune diseases.Bone Marrow Transplant. 2004; 33 ([abstract]): 346Google Scholar, 18Novik A. Ionova T. Bisaga G. et al.Clinical and quality of life responses to high-dose chemotherapy plus autologous stem cell transplantation in patients with multiple sclerosis: two case reports.Cytotherapy. 2005; 7: 363-367Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. "Early" HSCT (in MS patients with EDSS 1.5−3.0) is performed soon after diagnosis at early disease stage. "Conventional" HSCT (EDSS 3.5−6.5) is performed in patients with secondary refractory disease. "Salvage/late" HSCT (EDSS 7.0−8.0) is an option in case of high disease activity and rapid neurological deterioration in late stages of the disease. Analysis of treatment outcomes in these groups of patients will give background for the best candidates for HDIT + auto-HSCT. In this article, we report the follow-up results of the first arm of the study on the efficacy of HDIT + auto-HSCT. All 50 patients enrolled were administered the BEAM transplant regimen. The analysis is focused on long-term treatment outcomes in patients with different types and stages of MS. Fifty patients were enrolled in the study from 1999 to 2006 by five Russian centers. Patient characteristics are shown in Table 1. All patients previously underwent conventional therapy, which included interferon-β and mitoxantrone, as well as steroids, azathioprine, intravenous immunoglobulin, and plasmapheresis in some patients. Mean follow-up was 19 months (range, 6−90 months).Table 1Demographic and clinical profile of the patient populationNo. of patients50 (22 males)Age (y), median (range)32 (18−51)Type of disease SPMS27 PRMS1 PPMS11 RRMS11Disease duration (y), median (range)7.5 (1−14)Disability score (Kurtzke EDSS), median (range)5.0 (1.5−8.0)EDSS = Expanded Disability Status Scale; PPMS = primary progressive multiple sclerosis; PRMS = progressive relapsing multiple sclerosis; RRMS = relapsing-remitting course; SPMS = secondary progressive phase. Open table in a new tab EDSS = Expanded Disability Status Scale; PPMS = primary progressive multiple sclerosis; PRMS = progressive relapsing multiple sclerosis; RRMS = relapsing-remitting course; SPMS = secondary progressive phase. The trial was conducted according to the principles of the Helsinki Declaration. It was approved by Institutional Review Board and Ethics Committees of all participating centers before initiation. All patients gave written informed consent. The neurological disability of MS patients is quantified according to the EDSS [19Kurtzke J.F. Rating neurologic impairment in multiple sclerosis; an expanded disability status scale (EDSS).Neurology. 1983; 33: 1444-1452Crossref PubMed Google Scholar]. The EDSS scores range from 0 (no disability) to 10 (death related to neurological progression) in 0.5-step increments. EDSS scores from 1.0 to 4.5 refer to the fully ambulatory MS patients, while patients with EDSS scores of 7.0 are essentially restricted to a wheelchair. Criteria for patient selection were age between 18 and 55 years; diagnosis of MS verified by clinical and laboratory findings; progressive disease with registered disease activity, EDSS score 1.5 to 8.0; normal mental status; absence of severe concomitant diseases. Disease activity was determined either by magnetic resonance imaging scans displaying active lesions in the CNS (i.e., gadolinium-enhancing lesions, new or enlarging lesions on serial scans) or by clinical assessment showing rapid neurological deterioration, e.g., 0.5-point increase on the EDSS during the 6-months preceding enrollment. Three strategies of HDIT + auto-HSCT were employed: "early" transplantation (in MS patients with EDSS 1.5−3.0), "conventional" transplantation (EDSS 3.5−6.5) and "salvage/late" transplantation (EDSS 7.0−8.0) All three strategies were applied in this study (Table 2).Table 2Hematopoietic stem cell transplantation timing in the studied patient populationHSCT strategyEnrolled patientsAnalyzed patientsEarly HSCT (EDSS 1.5−3.0)9 patients (2 SPMS, 2 PPMS, 5 RRMS)6 patients (2 PPMS, 4 RRMS)Conventional HSCT (EDSS 3.5−6.5)37 patients (24 SPMS, 6 PPMS, 1 PRMS, 6 RRMS)35 patients (23 SPMS, 6 PPMS, 1 PRMS, 5 RRMS)Salvage HSCT (EDSS 7.0−8.0)4 patients (2 PPMS, 2 SPMS)4 patients (2 PPMS, 2 SPMS)EDSS = Expanded Disability Status Scale; HSCT = hematopoietic stem cell transplantation; PPMS = primary progressive multiple sclerosis; PRMS = progressive relapsing multiple sclerosis; RRMS = relapsing-remitting course; SPMS = secondary progressive phase. Open table in a new tab EDSS = Expanded Disability Status Scale; HSCT = hematopoietic stem cell transplantation; PPMS = primary progressive multiple sclerosis; PRMS = progressive relapsing multiple sclerosis; RRMS = relapsing-remitting course; SPMS = secondary progressive phase. Hematopoietic stem cells were mobilized with cyclophosphamide at 4 g/m2, followed by granulocyte colony-stimulating factor at 10 μg/kg according to EBMT/EULAR guidelines [20Tindall A. Gratwohl A. Blood and marrow stem cell transplants in autoimmune disease: a consensus report written on behalf of the European League against Rheumatism (EURAR) and the European Group for Blood and Marrow transplantation (EBMT).Bone Marrow Transplant. 1997; 19: 643-645Crossref PubMed Scopus (172) Google Scholar]. The grafts were not manipulated. BEAM or BEAM-modified conditioning was used. The BEAM conditioning regimen included BCNU (300 mg/m2) on day −6, etoposide (200 mg/m2) from day −5 to day −2, cytarabine (200 mg/m2) from day −5 to day −2 and melphalan (140 mg/m2) on day −1. It was followed by autologous hematopoietic stem cell transplantation (day 0). In vivo T-cell−depletion was achieved through infusion of 30 mg/kg of horse anti-thymocyte globulin on days 1 and 2. Five micrograms per kilogram (subcutaneous) of granulocyte colony-stimulating factor were administered from day 3 postinfusion until granulocyte recovery. For infection prophylaxis oral ciprofloxacin, fluconazole, acyclovir, and intravenous human immunoglobulin were given. Clinical evaluation was performed in accordance with the guidelines of EBMT [21Comi G. Kappos I. Clanet M. et al.Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation.J Neurol. 2000; 247: 376-382Crossref PubMed Scopus (87) Google Scholar]. In every center, neurological assessment was performed by one and the same neurologist at baseline, at discharge, at 3, 6, 9, and 12 months after transplantation, every 6 months thereafter up to 48 months, and then at yearly intervals. Neurological assessment included EDSS score and magnetic resonance imaging (MRI) examinations. According to EBMT criteria of response patients with steady EDSS scores representing halt of disease progression or with improved EDSS scores representing subsidence of inflammation in the CNS were regarded as responding to treatment [6Fassas A. Anagnostopoulos A. Kazis A. et al.Autologous stem cell transplantation in progressive multiple sclerosis—an interim analysis of efficacy.J Clin Immunol. 2000; 20: 24-30Crossref PubMed Scopus (165) Google Scholar, 7Fassas A. Passweg J.R. Anagnostopoulos A. et al.Haematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study.J Neurol. 2002; 249: 1088-1097Crossref PubMed Scopus (229) Google Scholar]. Clinical improvement was defined as a ≥0.5-point decrease in EDSS score as compared to the baseline. Progression was defined as an increase in 0.5 EDSS step for patients with initial EDSS >5.0 and an increase in 1.0 EDSS step for patients with initial EDSS <5.5. Both had to be confirmed after 6 months. Clinical relapse was defined as the appearance of new symptoms or worsening of old symptoms of at least 24 hours duration, in the absence of fever in a previously (4 weeks) stable patient. No toxic deaths were reported among 50 MS patients treated with BEAM regimen without graft manipulation, irrespective of their clinical condition at the time of transplant. Transplantation procedure was well-tolerated by the patients. Mobilization was successful in all cases with a median number of 2.1 × 106/kg (range, 1.5−5.5 × 106/kg) collected CD34+ cells; no major clinical adverse events were observed during this phase. Unmanipulated grafts were infused without complications. Engraftment was uneventful, and no signs of an engraftment syndrome were reported. Median days with polymorphonuclea neutrophils <0.5 × 109 and platelets 1.09SPMS, 4PPMS, 1PRMS, 1RRMS, 3Progression after improvement, n (%)2/28 (7.1)SPMS, 1RRMS, 1Stabilization, n (%)17/45 (37.7)SPMS, 9PPMS, 4RRMS, 4ProgressionaOne patient died of acute promyelocytic leukemia in 3 years after HDIT+ auto-HSCT. after stabilization, n (%)2/17 (11.8)SPMS, 1PPMS, 1auto-HCT = autologous hematopoietic stem cell transplantation; EDSS = Expanded Disability Status Scale; HDIT = high-dose immunosuppressive therapy; PPMS = primary progressive multiple sclerosis; PRMS = progressive relapsing multiple sclerosis; RRMS = relapsing-remitting course; SPMS = secondary progressive phase.a One patient died of acute promyelocytic leukemia in 3 years after HDIT+ auto-HSCT. Open table in a new tab auto-HCT = autologous hematopoietic stem cell transplantation; EDSS = Expanded Disability Status Scale; HDIT = high-dose immunosuppressive therapy; PPMS = primary progressive multiple sclerosis; PRMS = progressive relapsing multiple sclerosis; RRMS = relapsing-remitting course; SPMS = secondary progressive phase. All the patients responded to the treatment. Twenty-eight (28/45; 62.3%) improved by at least 0.5 point on the EDSS scale as compared to baseline (15 SPMS, 4 PPMS; 8 RRMS, and 1 PRMS). Eleven patients showed a 0.5-point EDSS improvement. Among them there were six SPMS, two PPMS, and three RRMS. However, one of them (RRMS) experienced a relapse 2.5 years after the transplantation and one (SPMS) progressed from EDSS 6.0 to 7.0 1 year after HSCT. Eight other patients had a 1.0-point decrease on the EDSS scale (six SPMS, two PPMS). Remarkably, nine patients improved dramatically. Patients with different types of MS were observed in this group: four SPMS, one PPMS, one PRMS, and three RRMS. As an illustration, in SPMS patient with the baseline EDSS value of 6.0 we observed a 2.0-point decrease on the EDSS scale at 1-month posttransplantation, an additional 1.5-point decrease at 6 months and stabilization with EDSS score of 1.5 at 18 months posttransplantation. In another case, RRMS patient with a baseline EDSS score of 4.5 experienced a decrease in EDSS to 2.0 at 1 month posttransplantation with an additional decrease to 1.0 at 3 months. The latter EDSS level remained stable throughout the entire follow-up period of 1.5 years. The PRMS patient with baseline EDSS value of 6.0 improved at 3 months to EDSS of 4.5 and then showed additional improvement at 30 months posttransplantation to the EDSS score of 4.0. The EDSS score at the end of follow-up (6.5 years posttransplantation) was 3.5. Finally, the PPMS patient with severe disease (EDSS score of 7.5) had a 1.5-point EDSS decrease and maintained this score during 3.5 years of follow-up. The remaining 17 patients (17/45; 37.7 %) had disease stabilization. This group included nine SPMS, four PPMS, and four RRMS. Only two patients had disease progression after stabilization. One of these patients (PPMS) progressed 18 months after transplantation. Another patient (female, 42 years old) with SPMS deteriorated from EDSS 6.5 to 7.0 12 months after transplantation. Two gadolinium-enhancing lesions were present on MRI. After treatment with methylprednisolone followed by two single doses of mitoxantrone (10 mg/kg at 14 and 18 months posttransplantation), slight neurological improvement was observed. Her blood count was normal during the above mentioned follow-up. At 43 months after HDIT + auto-HSCT acute promyelocytic leukemia developed and the patient died of cerebral hemorrhage. This is the only case of death at long-term follow-up after HDIT + auto-HSCT. To interpret this information, additional studies are worthwhile. Results of MRI scans were available in 37 patients. Sixteen patients (43.3%) had active lesions at baseline and all turned to inactive status except two. Of 21 patients without active lesions pretransplantation, 20 remained inactive, whereas 1 patient showed disease activity after transplantation. No active, new, or enlarging lesions were registered in patients without disease progression. As it is seen from Table 3, nine patients with PPMS were included in the efficacy analysis with their baseline EDSS varying from 3.0 to 8.0. As the result, five patients improved and four patients experienced stabilization. Only one patient in this group had disease progression after 18 months. Out of 4 patients having severe disability with EDSS 7.0 to 8.0, two patients (PPMS and SPMS) experienced improvement and two others stabilized (PPMS and SPMS). Of special interest is the group of patients that underwent "early" transplantation (mean age 28 years; median EDSS 2.0). All six patients included in the analysis responded to treatment. Five patients had a 0.5-point decrease on the EDSS scale already 3 months posttransplantation, which remained stable during the follow-up in all the patients except one (male, 25 years old) who relapsed 2.5 years after transplantation. One patient (female, 31 years old) experienced a remarkable decrease of EDSS from 3.0 at baseline to 1.5 at 3 months posttransplantation. At 18 months after transplantation, an additional decrease of EDSS by 0.5 took place. Progression-free survival at 6 years after HDIT + auto-HSCT was 72% (Fig. 1). All patients who did not have disease progression were off therapy throughout the posttransplantation period. MS is a chronic incurable disease of the CNS and conventional therapies do not provide satisfactory control of this disease. At present, HDIT + auto-HSCT is considered as a treatment option for severe autoimmune diseases, including MS [22Brenner M.K. Haematopoietic stem cell transplantation for autoimmune disease: limits and future potential.Best Pract Res Clin Haematol. 2004; 17: 359-374Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 23Saccardi R. Kozak T. Bocelli-Tyndall C. et al.Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database.Mult Scler. 2006; 12: 814-823Crossref PubMed Scopus (186) Google Scholar]. Taking in account good perspectives of the method in MS patients, a number of studies to have better understanding of the processes following HDIT + auto-HSCT, from the mechanisms of immune system restoration [15Sun W. Popat U. Hutton G. et al.Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis.Brain. 2004; 127: 996-1008Crossref PubMed Scopus (82) Google Scholar, 24Muraro A.P. Douek D.C. Packer A. et al.Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients.J Exp Med. 2005; 201: 805-816Crossref PubMed Scopus (374) Google Scholar] to brain-volume changes after treatment [25Inglese M. Mancardi G.L. Pagani E. et al.Brain tissue loss occurs after suppression of enhancement in patients with multiple sclerosis treated with autologous haematopoietic stem cell transplantation.J Neurol Neurosurg Psychiatry. 2004; 75: 643-644PubMed Google Scholar], were performed. Published clinical results demonstrate that this approach can stop disease progression in a majority of patients. A comprehensive analysis of the EBMT registry data of 85 patients from 20 centers published by EBMT Autoimmune Diseases Working Party in 2002, showed no disease progression for 3 years in 74% of patients [7]. The results were confirmed by the recent report of EBMT Autoimmune Diseases Working Party [23Saccardi R. Kozak T. Bocelli-Tyndall C. et al.Autoimmune Diseases Working Party of EBMT. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database.Mult Scler. 2006; 12: 814-823Crossref PubMed Scopus (186) Google Scholar]. Similar results were obtained in five US studies, which included 66 patients in total [9Openshaw H. Lund B. Kashyap A. et al.Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning report of toxicity and immunological monitoring.Biol Blood Marrow Transplant. 2000; 25: 525-575Google Scholar, 10Burt R.K. Cohen B.A. Russell E. et al.Hematopoietic stem cell transplantation for progressive multiple sclerosis; failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores.Blood. 2003; 102: 2373-2378Crossref PubMed Scopus (172) Google Scholar]. Remarkably, transplantation-related mortality in MS patients does not exceed transplantation-related mortality in hematological patients (0−4%). Results our study have also demonstrated the benefits of HDIT + auto-HSCT in MS. Fifty patients with various types of MS from five centers were included in the study. As a result, no toxic deaths were reported among 50 MS patients treated with BEAM regimen without graft manipulation, irrespective of their clinical condition at the time of transplantation, and transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients monitored for at least 9 months. It is worth mentioning that all the patients responded to treatment. In 28 patients EDSS score decreased after HDIT + auto-HSCT as compared to baseline and it was confirmed during 6 months; disease stabilization (stable EDSS after transplantation confirmed during 6 months) was registered in 17 patients. Four patients progressed at different time points posttransplantation; two after improvement and two after stabilization. No gadolinium-enhancing, new, or enlarging lesions were registered in patients without disease progression. Progression-free survival at 6 years after HDIT + auto-HSCT was 72%. These data strongly support use of HDIT + auto-HSCT as the therapy of choice in autoimmune diseases with imminent patient debilitation, such as MS. It is worth mentioning that the issues surrounding patient-selection criteria for HDIT + auto-HSCT are still unclear. The information about the outcomes of HSCT in patients with various types of MS is limited. The advantage of our study is that we included patients with different types of MS. In spite of some evidence that PPMS patients are less responsive to HDIT + auto-HSCT as compared to both SPMS and RRMS [7], our data showed positive results for PPMS. It is really remarkable that of nine patients with PPMS included in the efficacy analysis with their baseline EDSS varying from 3.0 to 8.0, five patients improved and four patients experienced stabilization. Only one patient in this group had disease progression after 18 months. The results of our study confirm that transplantation might be effective in PPMS patients and patients with different types of MS might benefit from HDIT + auto-HSCT. Another advantage of our study is that we applied HDIT + auto-HSCT for patients in different stages of the disease. According to our hypothesis, there could be determined three treatment strategies that should be analyzed separately: "early," "conventional," and "salvage/late" transplantation. "Early" HSCT is performed soon after diagnosis in early disease stage and is meant for patients with EDSS 1.5 to 3.0. Its goal is to prevent irreversible CNS damage by the immunopathological process, to preserve patient's quality of life, and to prevent his/her disability. "Conventional" HSCT is performed in patients with EDSS 3.5 to 6.5 who have secondary refractory disease and is meant to prevent disease progression in patients with CNS damage and partial loss of neurological function as well as to improve the patient's quality of life, preserve it at the maximal possible level and prevent worsening of patient's disability. "Salvage/late" HSCT is an option in case of high disease activity and rapid neurological deterioration in late stages of the disease (EDSS 7.0−8.0) and aims to stop the disease progression in patients with irreversible CNS damage and significant loss of neurological function. It may be considered as a last chance to preserve the patient's quality of life at the maximal possible level and to prevent his/her critical disability. It is worth mentioning that in previous studies most patients had late stages of MS. Our data support the idea that HDIT + auto-HSCT is more effective in young patients with early stages of rapidly progressing disease [11Fassas A. Nash R. Multiple sclerosis.Best Pract Res Clin Hematol. 2004; 17: 247-262Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. In these patients, autoreactive T cells play a pivotal role in MS pathogenesis. HDIT ablates the patient's immune system and eradicates autoimmune T cells. It is followed by HSCT to restore the immune system, which is expected to become tolerant to autoantigens. Such "resetting" of the immune system is only effective at early stages of MS, particularly in relapsing-remitting MS. Later in the clinical course of the disease, processes of axonal degeneration prevail and damage to CNS tissue is too significant to expect a neurological recovery after HDIT + auto-HSCT. The rationale of early transplantation is supported by the data on the occurrence and characteristics of myelin-reactive T cells during reconstitution of the immune system following transplantation in severely disabled MS patients with long disease course [15Sun W. Popat U. Hutton G. et al.Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis.Brain. 2004; 127: 996-1008Crossref PubMed Scopus (82) Google Scholar]. Indeed, failure of HDIT + auto-HSCT to prevent progression of the disease when performed in the late stages has been demonstrated in both animal models [26Burt R.K. Padilla J. Begolka W.S. et al.Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis.Blood. 1998; 91: 2609-2616PubMed Google Scholar] and in clinical studies [12Nash R.A. Bowen J.D. McSweeney P.A. et al.High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis.Blood. 2003; 102: 2364-2372Crossref PubMed Scopus (198) Google Scholar, 27Burt R.K. Cohen B. Lobeck L. Traynor A.E. Autologous haematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome.Neurology. 2003; 40 ([abstract]): A150Google Scholar]. This study has several limitations. The first limitation is that the number of patients in groups with different strategies of HDIT + auto-HSCT, namely "early," "conventional," or "salvage/late" transplantation, is quite low. Also, the observation period is not long enough: mean follow-up was 19 months and less than half of the patients had been observed for more than 3 years. Finally, in this article we report the results of one arm of the study: all the patients received the BEAM-conditioning regimen. Taking into account that nonmyeloablative transplant regimens will be associated with less morbidity and mortality, information about treatment outcomes in patients who underwent nonmyeloablative transplant regimens is worthwhile. We hope to be able to provide analysis of the second treatment arm in the nearest future. In conclusion, our study has demonstrated that HDIT + auto-HSCT may be an effective treatment for various types of MS at long-term follow-up. A randomized, comparative trial will be able to confirm the efficacy of the new approach for MS treatment. The rationale of evolution from myeloablative to nonmyeloablative transplant regimens should be confirmed by the further studies. We thank Alexandr A. Myasnikov (Petrozavodsk), Gennadiy I. Bisaga (St. Petersburg), Nikolay I. Baziy (Moscow), Anton V. Kishtovich (St. Petersburg), and Artur E. Zdorov (Petrozavodsk) for their participation in data collection. The authors declare no competing financial interests.
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